In the United States and Western Europe, cardiovascular disease and its associated maladies, dysfunctions and complications are a principal cause of disability and the chief cause of death. One specific entity significantly contributing to this pathophysiologic process is atherosclerosis, which has been generally recognized as the leading health care problem both with respect to mortality and health care costs. The American Heart Association estimates that 953,110 persons died of cardiovascular diseases in 1997 (41.2 percent of all deaths), more than the number of mortality for cancer (539,377), accidents (95,644) and HIV (16,516) combined. Furthermore, the American Heart Association calculates that close to a quarter of the population of the United States suffers from one or more forms of cardiovascular disease. Moreover, the medical costs associated with coronary heart disease are estimated at $95 billion dollars a year. Gonzalez & Kannewurf, 55 (19) American Journal of Health-System Pharmacy S4-7 (Supp. 1, 1998).
Atherosclerosis is a disease characterized by the deposition of fatty substances, primarily cholesterol, and subsequent fibrosis in the inner layer (intima) of an artery, resulting in plaque deposition on the inner surface of the arterial wall and degenerative changes within it. The ubiquitous arterial fatty plaque is the earliest lesion of atherosclerosis and is a grossly flat, lipid-rich atheroma consisting of macrophages (white blood cells) and smooth muscle fibers. The fibrous plaque of the various forms of advanced atherosclerosis has increased intimal smooth muscle cells surrounded by a connective tissue matrix and variable amounts of intracellular and extracellular lipid. At the luminal surface of the artery, a dense fibrous cap of smooth muscle or connective tissue usually covers this plaque or lesion. Beneath the fibrous cap, the lesions are highly cellular consisting of macrophages, other leukocytes and smooth muscle cells. Deep in this cell-rich region may be areas of cholesterol crystals, necrotic debris and calcification.
If allowed to progress, the disease can cause narrowing and obstruction of the lumen of the artery, diminished or occluded blood flow and, consequently, ischemia or infarction of the predominantly affected organ or anatomical part, such as the brain, heart, intestine or extremities. The result can be significant loss of function, loss of cellular substance, emergency medical and/or surgical procedures, and significant disability or death. Alternatively, the arterial wall can be severely weakened by the infiltration of the muscular layer with the lipid (cholesterol), inflammatory white blood cells, connective tissue and calcium, resulting in soft and/or brittle areas which can become segmentally dilated (aneurysmal) and rupture or crack leading to organ, limb or even life-threatening hemorrhage.
Ischemic heart disease is the most common cause of morbidity and mortality in the population over the age of sixty-five. Sullivan, L. W. 1990. Healthy people 2000. N Engl J Med. 323:1065–1067; Wei, J. Y. 1992. Age and the cardiovascular system. N Engl J Med. 327:1735–1739; Association, A. H. 1993–1995. Heart and stroke facts statistical supplement/1994–1996. Dallas, Tex.: The Association. Elucidation of the cellular and molecular pathways that are impaired with aging is critical to the development of specific strategies to prevent and reduce the pathology of cardiovascular disease associated with advancing age.
In younger individuals, myocardial ischemia induces the development of a collateral vasculature supply that partially protects the cardiac tissue from subsequent coronary events. Hirai et al. (1989) Circulation. 79:791–796; Ejiri et al. (1990) J Cardiol. 20:31–37; Kodama et al. (1996). J Am Coll Cardiol. 27:1133–1139; Banerjee et al., (1993) Int J Cardiol. 38:263–271. However, angiogenesis is impaired in older heart and peripheral vascular beds. Hudlicka et al. (1996) J Vasc Res. 33:266–287; Isoyama (1994) Drugs Aging. 5:102–115; Tomanek et al. (1990) Am J Physiol. 259:H1681–1687; Anversa et al. (1994) Am J Physiol. 267:H1062–1073; Azhar et al. (1999) Exp Gerontol. 34:699–714; Rakusan et al. (1994) Cardiovasc Res. 28:969–972; Rivard et al. (1999) Circulation. 99:111–120; Reed et al. (2000) J Cell Biochem. 77:116–126. The etiology of the impaired angiogenic activity in the senescent heart and within aging blood vessels is not known. In fact, despite recent advances in our understanding of the molecular pathways regulating angiogenesis during embryonic development, the mechanistic alterations in angiogenic function in the senescent vasculature are not well understood.
The etiology of atherosclerotic plaques is similarly a matter of debate and uncertainty. Much research in recent years has focused upon the molecular pathways of cholesterol deposition and upon altering serum lipoprotein concentrations for achieving therapeutic effect. Goldstein et al., Science 292: 1310–12. There has been speculation that the replicative senescence of vascular endothelium plays a role in the etiology of atherosclerosis. Chang et al., 1995 Proc. Natl. Acad. Sci. 92:11190–94. Moreover, studies show that telomere length can determine the lifespan of cells. Bodnar et al., 1998 Science 279: 349–53. In addition, cells with a morphology similar to senescent cells co-localize with mature atherosclerotic plaques. Osamu et al., 1989 Am. J. Pathol. 135: 967–76. However, methods for grafting young vascular endothelial cells into an old animal have been unavailable.
Therefore, new approaches are needed for counteracting the age-associated changes in angiogenic pathways and the repair of endothelium within senescent vascular tissues.